Halogenated 4-(4&#39;-bisphenylyl)-butanols

ABSTRACT

Compounds of the formula   WHEREIN R1 is halogen or amino, R2 is hydrogen or halogen, and R3 is hydrogen or hydroxyl, AND, WHEN R1 is amino, non-toxic, pharmacologically acceptable acid addition salts thereof; the compounds as well as the salts are useful as antiphlogistics.

United States Patent 1 Teufel et al.

[ J-an.7, 1975 221 Filed: 0:.10,1972

21 Appl. No.: 295,880

[30] Foreign Application Priority Data Oct. 15.1971, Germany 2151311 [521' US. Cl. 260/618 D, 260/254, 260/50l.l,

260/515 R, 260/515 A, 260/518 R, 260/518 A. 260/519, 260/520, 260/571, 424/330, 424/343 [51] Int. Cl. C07c 31/14 [58] Field of Search 260/618 D [56] References Cited UNITED STATES PATENTS 3.801.654 v 4/1974 Seeger et a1. 260/618 R Primary ExaminerJoseph E. Evans Assistant Examiner-D. B. Springer Attorney, Agent, or Firm-Hammond & Littell ABSTRACT Compounds of the formula wherein R, is halogen or amino,

R is hydrogen or halogen, and

R is hydrogen or hydroxyl,

and, when R is amino, non-toxic, pharmacologically acceptable acid addition salts thereof; the compounds as well as the salts are useful as antiphlogistics.

2 Claims, No Drawings HALOGENATED 4-(4'-BIPHENYLYL)-BUTANOLS This invention relates to novel 4-(4-biphenylyl)- butanols, as well as to various methods of preparingthese compounds.

More particularly, the present invention relates to a novel class 4-(4'-biphenylyl)-butanols. of the formula wherein R, is halogen or amino,

wherein R, and R have the meanings defined in connectionwith formula I, with a complex hydride in the presence of an inert organic solvent medium at atemperature between room temperature and the boiling point of the particular solvent medium which is used.

Examples of suitable complex hydrides are lithium aluminum hydride, which is especially preferred, lithium borohydride, sodium bis-(B-methoxy-ethoxy)- dihydroaluminate and sodium aluminum hydride.

Examples of suitable solvent media are tetrahydrofuran, ether, dioxane, dimethoxy-ethane, diethyleneglycol dimethyl ether, benzene and mixtures of any two or more of these. Method B For the preparation of a compound of the formulail wherein 1 R is hydroxyl, by biphenylyl)'4-oxo-butyric acidof the formula (III) wherein R, and R have the same meanings as in for mula I, with a complex hydride, preferably-lithium alu-. minurn hydride, under the conditions described in method A.

The starting compounds of the formula 11 may be obtained. for instance, by catalytic hydrogenation of a 4- (4-biphenylyl)-4-oxo-butyric 'acid of the formulaIII in a polar solvent, such as glacial acetic acid, in the pres- I ence of a strong acid, such as perchloric acid, at a temperature between and 50C. and a hydrogen pressure of 1 to 5 atmospheres with palladized barium sulfate or palladized charcoal as the catalyst (cf. also German Offenlegungsschrift 2,1 12,840). A 4-(4-biphenylyl)-4- oxo-butyric acid of the formula III, in turn, may be obtained by reacting a correspondingly substituted biphenyl with succinic acid anhydride in the presence of a Lewis acid, such as anhydrous aluminum chloride, in a solvent medium, such as nitrobenzene or methylene chloride, at a temperature between 0 and 80C. (cf. also German Offenlegungsschrift 2,112,716); in those instances where the biphenyl starting compound is an amino-substituted biphenyl, the amino-substituent must be acylated prior to the reaction with the succinic acid anhydride. After completion of the reaction, the protective acyl group may then be split off again by conventional methods.

Those compounds of the formula I wherein R, is amino are organic bases and therefore form acid addition salts with inorganic or organic acids. Examples of non-toxic, pharmacologically acceptable acid addition salts are those formed with hydrochloric acid, hydrobr'omic acid, sulfuric acid, acetic acid, 8- chlorotheophylline or the like.

The following examples further illustrate the present invention and will enable others skilled in the art to understand it more completely. It should be understood,

however, that the invention is not limited solely to the particular examples given below.

, EXAMPLE 1 4-(2"-Fluoro-4'-biphenylyl)-1.-butanol by method A 1.13 gm (0.03 mol) of lithium aluminum hydride were gradually added to a solution of 7.74 gm (0.03

mol) of 4-(2"-fluoro-4'-biphenylyl)-butyric acid (m. p.

f-66C.) in 100 ml of absolute .tetrahydrofuran,

while stirring,and the resulting mixture was refluxed for 4 hours. Thereafter, the reaction mixture was al- .lowed tocool, was then admixed with ice water, and

Hg and a melting point of 32-34C. after crystallizareducing a 4-(4' tion from petroleum ether. It was identified to be the compound of the formula EXAMPLE 2 Using a procedure analogous to that described in Example 1, of theory-of 4-(4"-fluoro-4' biphenylyl)- 1-butanol, b. p. 143-145C. at 0.2 mm Hg, m. p. 73C.. (from cyclohexane/petroleum ether), was obtained from 4-(4"-fluoro-4'-biphenylyl)-butyric acid (in. p. 1 19-120C and lithium aluminum hydride.

EXAMPLE 3 4-(2''-Chloro-4-biphenylyl)-l-butanol by method A Asolution of 25 gm (0.0912 mol) of 4-(2"-chloro- 4-biphenylyl)'-butyric acid (m. p. 6l-62C.) in ml of absolute ether was added dropwise to a suspension of 3.8 gm (0.1 mol) of lithium aluminum hydride in300 ml of absolute ether at room temperature, while stirw -ouvofont-onion which had a boiling point of 160C. at 0.1 mm Hg.

EXAMPLE 4 Using a procedure analogous to that described in Example 3, 69% of theory of 4-(4" chloro-4-biphenylyl)- l-butanol, b. p. 170C. at 0.15 mm Hg, m. p. 9798C., was obtained from 4-(4"-chloro-4-biphenylyl)-butyric acid (in. p. 1369-137C.) and lithium aluminum hydride with tetrahydrofuran as the solvent medium.

EXAMPLE 5 4-(2"-Amino-4-biphenylyl)-l-butanol by method A A solution of 8 gm (0.03l3imol) of 4-(2-amino-4- b iphenylyU-butyric acid in 50 ml of anhydrous ether was added dropwise to a suspension of 2.3 gm (0.062

mol) of lithium aluminum hydride in 200 ml of anhy drous ether at room temperature, while stirring, and the resulting mixture was refluxed for 3 hours. Thereafter, the reaction mixture was allowed to cool, unreacted excess lithium aluminum hydride was decomposed by addition of a little ethyl acetate, the mixture was poured into ice water, and the aqueous mixture was acidified with aqueous 5.0% sulfuric acid, then made alkaline with aqueous 30% sodium hydroxide and extracted three times with ether. The ethereal phases were combined, dried over sodium sulfate and freed from ether by evaporation. The oily residue was distilled in vacuo', yielding 4 gm of a distillatehaving a boiling point of l79l 80C. at 0.3- mm Hg which solidified upon standing and had a melting point of 70-72C. after recrystallization from cyclohex- Y ane/ethyl acetate. It was identified to be the compound of the formula Its hydrochloride had a melting point of 205C/(decomp'.).

EXAMPLE 6 l-(2 -Fluoro-4 -biphenylyl)-l ,4-butanediol by method B 20.4 gm (0.075 mol) of 4-(2"-fluoro-4f-biphenylyl)- 4-oxo-butyric acid (m. p. l6ll62C.) were gradually added to a suspension of 5.7 gm (0.15 mol) of lithium aluminum hydride ,in 100 ml of absolute tetrahyd'rofuran at room temperature, while stirring, and the resulting mixture was refluxed for-4 hours. Thereafter, the reaction mixture was-allowed to cool, unreacted excess lithium aluminum hydride was decomposed by ad- I dition of a little ethyl acetate, the mixture was poured into ice water, and the aqueous mixture was acidified with aqueous 50% sulfuric acid and then extracted with ether. The etherealphase was washed with water, dried andfreed from'ether by evaporation. The oily residue was distilled in vacuo, yielding 15.5 gm (79.5% of theory) of a substance having a boiling point of 196C. at

O.l mm Hg which, upon recrystallization from cyclohexane/ethyl acetate. had a melting point of 8889C. lt wasidentified to he the compound of the formula Q-Q-{on-orrg-orh-omon EXAMPLE? I Using a procedure analogousto that described in Example 6, except that the reaction mixture was refluxed for only 1 hour, 78% of theory ofl-(2"-chloro-4'- biphenylyl)-1,4-butanediol, m. p. 8889C. (from cyclohexane/ethyl acetate), of the formula was obtained from 4-( 2 '-chloro-4 '-biphenylyl)-'4-oxo- 1 butyric acid (m. p. l72l74C.) and lithium aluminum hydride.

EXAMPLE 8 Using a procedure analogous to thatdescribed in Example 6, of theory of l-('4"-chloro-4'-biphenylyl)- 1,4-butanediol, m. p. l2l.-l-22,C. (from cyclohexane/ethyl acetate),.was obtained from 4-(4 "-chloro-4- biphenylyl)-4-oxo-butyric acid (m. p. 188C.) and lith-'- ium aluminum hydride.

EXAMPLE 9 l Using a procedure analogous to thatdescribed in Example 6, 58% of theory of l-(4"-fluoro-4'-biphenylyl)- 1,4-butanediol, b. p. l90-l92C. at 0.2mm Hg, m. p. ll2-ll4C." (from diisopropyl ether), was obtained from 4-(4"-fluoro-4-biphenylyl)-4-oxo-butyric acid (m. p. 177l7 8C.) and-lithium aluminum hydride.

EXAMPLE 10 Using a procedure analogous to that described in Example 6,- 60% of theory of 1-(2f ',4"-dichloro-4'- .biphenylyl-)-l ,4-butanediol, m. p. 98C., of the formula was obtained from 4-(2",4"-dichloro-4'-biphenylyl)- 4-oxo-butyric acid (m. p. l52l 53C.) and lithium aluminum hydride.

EXAMPLE 11 l-(2",3"-Dichloro-4-biphenylyl)-1,4-butanediol by method B 16.2 gm (0.05 mol) of 4-(2,3"-dichloro-4'- biphenylyl)-4-oxo-butyric acid (m. p. 174C.) were gradually added to a suspension of 3.8 gm (0.1 mol) of lithium aluminum hydride in 250 ml of tetrahydrofuran at room temperature, while stirring, and the resulting mixture was refluxed for 1 hour. Thereafter, the'reaction mixture was worked up as described in Example 6. The oily residue obtained thereby was dissolved in a small amount of ethyl acetate, the solution was heated to its boiling point, and petroleum ether was added to the boiling solution until it became turbid. Upon cooling, 13 gm (84% of theory) of a colorless crystalline substanceseparated out which had a melting point of 8789C. It was identified to be the compound of the 1 formula EXAMPLE 12 350 gm (0.12l mol) of4-(3"-chloro-4'-biphenylyl)- added to a suspension of 10.4 gm (0.274 mol) of lithium aluminum hydride in 185 ml of absolute tetrahydrofuran at room temperature, while stirring, and the resulting mixture was stirred for 4 hours at an internal temperature of 40C. Thereafter, ml of ethyl acetate were added, the mixture was again stirred for 1 hour at 40C., and then the major amount of the tetrahydrofuran was distilled off in vacuo. The precipitate formed thereby was caused to go back into solution by the addition of 250 ml of aqueous 1 0% sulfuric acid, the solution was extracted several times with ether, and the combined ethereal extracts were washed successively with water, saturated aqueous sodium bicarbonate and water. The organic phase was dried over sodium sulfate, filtered, and the filtrate was evaporated in vacuo. The light brown, crystallizing residue was chromatographed on a total of 2 kg of silica gel with ethyl acetate/benzene (5:1) as the solvent. The combined eluates were evaporated, and the residue was recrystallized once from benzene and oncefrom tetrachloromethane, each time in the presence of activated charcoal, yielding 25.0 gm (74% of theory) of the colorless crystalline compound of the formula 4-(3"-Ch1oro 4'-biphenylyl) l-butanol by method A A solution of 30.0 gm (0.109 mol) of 4-(3"-chloro- 4'-biphenylyl)-butyric acid (m. p. 80-81C.) in 50 ml 4-0xo-butyric acid (m. p. l46-147C.) were gradually of absolute tetrahydrofuran was added dropwise to a suspension of 4.55 gm (0.120 mol) of lithium alumi- A num hydride in m1 of absolute tetrahydrofuran at room temperature, while stirring, and the mixture was stirred for 4 hours at 40C. Thereafter, 10 ml of ethyl acetate were added dropwise, the resulting mixture was again stirred for 1 hour at 40C., the major amount of the tetrahydrofuran was evaporated in a water aspirator vacuum, and'the residue was caused to go into solution by addition of 100 ml of aqueous 10% sulfuric acid. The resulting solution was thoroughly extracted with ether, the combined ethereal extracts were successively washed with water, saturated aqueous sodium carbonate and water, dried over sodium sulfate and filtered. The filtrate was evaporated in vacuo, and the residue was distilled in vacuo, yielding 75% of theory of a colorless oil which had a boiling point of l62-165C. at 0.1 mm Hg and crystallized upon cooling. The crystalline product had a melting point of 2324C., n 1.6031 (subcooled melt). It was identified to be the compound of the formula cm msca cm biphenylyl)-butyric acid (m. p. 63C.) in 50 ml of absolute ether was added dropwise to a suspension of 1.5 gm (0.04 mol) of lithium aluminum hydride in ml of absolute ether at room temperature, while stirring, and the resulting mixture was stirred for 2 hours more at room temperature. Thereafter, 2 ml of water, then 2 ml of 2N sodium hydroxide and again 6 ml of water were added, and the precipitate formed thereby was collected by vacuum filtration. The ethereal phase of the filtrate was separated, dried, the ether was evaporated, and the oily residue was distilled in vacuo, yielding 7.5 gm (82% of theory) of a substance having a boiling point of'l80-l82C. at 0,6 mm Hg which was identified to be the compound of the formula The compounds of the present invention, that is,

those embracedby formula I above and, when R is amino, non-toxic acid addition salts thereof, have useful pharmaeodynamic properties. More particularly, 5 they exhibit very effective antiphlogistic activity in The compounds were tested for their anti-exudative effects on the kaolin edema and carrageenin edema of weight of 130 to 150 gm. The animals were given the substances on three subsequent days, once each day, as

a trituration in tylose by way of an esophageal tube.

The animals were killed 4 hours after'the last adminfilp li l zl phenylbutijlzgned d h 5 istration; the stomach and duodenal mucosa were ine ao in e ema was in uce accor mg to t e vestigated for lce I z gz g Hllljlelbrecht l f l l g 'gs l 'f 1 From thebercentage of animals showing ulcers after iuspenlliony31:53:22zi gg sgdiuin c210 3d: Solu" administration of different doses, the -ED -}\1 talue was 0 l ulated ccordin to the method of Lite ield and tion. The measurement of the thickness of the paws was 10 w f 3 ph i L exp Therap 9 99 1949)] done by the techmque of Doepfnr and Cerlem After oral administration to male and female FW 49- RZ- l ga z g ylnflmunol- 89 0: prats (ratio 1 :1) havingan average body weight of 135 a e 0 f z welg t 0 120450 gm, the acute toxic ty (LD was determined. The subgg g fg g z z f ssi gg sfig i gs I5 stances were administered orally as a trituration in tylose. ofan so ha eal tub r. t the ecfem a tlfe avera ilzl uzs faflll ss efiliz db u l cl The calculatlon of the LBW-values was effected as in the aws of the rat treated with the test C051 ounds far as possible according to the method of Li'tChfiel-d were c bm ared with those values measured on blindand wilcoxon based on the percentage of animals p which died within 14 days after administration of the treated control animals. By graphic extrapolation the different doses r v dose leading to a 35% reduction of the swelling (ED was calculated from the percent reduction values mea-' h therapeutic mdlces, as almeasul'e j sured by administration of different doses. R f g g f f ig by l l t e 2. 3? The provocation of the carrageenin edema was ef- E3" 0 e 'g' or l g l y fected according to the method of Winter et a1. [Proc. I f Us 3" t 3 2 S 5cm exp. Biol- Med. 111, 544 (1962)] by subpla-mary or anti-izxu ative activity agains e a0 in an ca ainjection of 0.05 ml of a 1% solution of carrageenin in geenm m v I a 0.85% solution of sodium chloride. The test com- The above-mentioned compounds surpass the known pounds were orally administered 60 minutes before the c mpo n p e y butazone. in h ir antiphlogistic acprovocation of the edema, v tivity (see Table I). In comparison with phenylbutazone dFor ttl'ihe calculation of 'tihg ri'leductiyte etfrfect on the tit tey posses: a lower toiiclilty atnd exirt a less impairing e ema e va ues measure oursa er e provocae ect ont e mucosa o te s omac tion of the edema we're used. All the other details were The resulting substantially more favorable therapeuthe same as described above in the case of the kaolin tic indices (see Table 11) point to a significantly better edema. therapeutic usefulness as compared with phenylbuta- The tests for ulcerogenic activity' were effected on zone, which is known to be compatible with the stom- FW 49-rats of both sexes (ratio 1:1) having a body. ach only on a very limited scale.

TABLE 1 Compound kaolin edema carrageenin acute toxicity ulcerogenicity ED per os edema in the rat in the rat mgm/kg 11D, per os LDM per os ED per os .nigm/kg mgm/kg confidence limits mgm/kg' confidence lin its (%probability) (95% probability) Phenylbutazone 'ss 69 864 793-942 106 82-138 A 22 16.5 1120 889-1411 96 74-125- a s4 60 2100 1992-2331 200 143-280 c -31 56 2840 2309-3493 400* D so 46 1680 12354285 111-246 E 27 33 800 661-880 74 64-85 After 200 mgm/kg. 3 out of 20 animals had ulcers; after 400 mgm/kg, 6 out of 20 animals had ulcers.

TABLE 11 Compound antiexudative acute toxicity I ulcerogenic therapeutic index effect effect i ED nigm/kg" LD mgm/kg ED mgm/kg -ratio of toxic ratio of ulcerogenic and antiexudative and antiexudative effect effect M m/EDns .Phenylbutazone 63.5 864 106 13.6 1.7

A 19.3 1120 I 96 58.0 5.0 B 57 2100 200 36.8 3.5 C 43.5 2840 400 65.3 9.2 D 48 1680 165 35.0 3.4 E 30 800 74 26.7 2.5

arithmetically averaged value from ED for kaolin edema and ED for cariageenin edema For pharmaceutical purposes the compounds according to the present invention are administered to warmblooded animals perorally or parenterally as active ingredient's in customary dosage unit compositions, that is, compositions in dosage unit form consisting essentially of an inert pharmaceutical carrier and one effective dosage unit of the active ingredient, such as tablets, coated pills, capsules, wafers, powders, solutions, suspensions, emulsions, syrups, suppositories and the like. One effective anti-phlogistic dosage unit of the compounds according to the present invention is from 0.83 to 6.67 mgm/kg body weight, preferably 1.33 to 5.0 mgm/kg body weight. The daily dose rate is from 1.66 to 16.7 mgm/kg body weight, preferably 2.5 to 10 mgm/kgbody weight.

The following examples illustrate a few pharmaceuti- .cal dosage unit compositions comprising a compound of the present invention as an active ingredient and represent the best modes contemplated of putting the invention into practical use.,The parts are parts by weight unless otherwise specified.

EXAMPLE Tablets The tablet composition is compounded from the following'ingr'edients:

4 t 2 '-Fluoro-4 -biphenylyl)- l -butanol 200.0 parts Corn starch 97.0 do. Polyvinylpyrrolidone 10.0 do. Magnesium stearate 3.0 do.

Total 310.0 parts Preparation The butanol compound and the corn starch are intimately admixed with each other, the mixture is granulated with an aqueous 14% solution of the polyvinylpyrrolidone through a 1.5 mm-mesh'screen, the granulate is dried at 45C. and again passed through the screen, the dry granulate is admixed with the magnesium stearate, and the composition is compressed into 310 mgm-tablets in a conventional tablet making machine. Each tablet contains 200 mgm of the butanol compound and is an oral dosage unit composition with effective antiphlogistic action.

EXAMPLE 16 Coated Pills The pill core composition is compounded from the following ingredients:

4-(2"-Fluoro-4'-biphenylyl)-1-butanol 200.0 parts Corn starch 7 70.0 do. Gelatin 8.0 do. Talcum 18.0 do. Magnesium stearate 4.0 do.

Total 300.0 parts Preparation a thin shell consisting essentially of a mixture of sugar and talcum and finally polished with beeswax. Each coated pill contains 200 mgm of the butanol compound and is an oral dosage unit composition with effective anti-phlogistic action.

EXAMPLE 17 Gelatin Capsules The capsule filler composition is compounded from the following ingredients:

1-(2"-Fluoro-4'-biphenylyl) 1.4- 200.0 parts butanediol Corn starch 190.0 do.

Colloidal silicic acid 6.0 do.

Magnesium stearate 4.0 do.

Total 400.0 parts Preparation v The ingredients are intimately admixed with each other, and 400 mgm-portions of the mixture are filled into No. l gelatin capsules. Each capsule contains 200 mgm of the butanediol compound and is an oral dosage unit composition with effective antiphlogistic action.

EXAMPLE 18 Suppositories The suppository composition is compounded from the following ingredients:

1-(2"-Fluoro-4'-biphenylyl)-1,4- 300.0 parts butanediol Suppository base (e.g. cocoa butter) 1450.0 do.

Total 1750.0 parts EXAMPLE 19 Suspension I The suspension is compounded from the following ingredients:

1-(2"-Fluoro-4'-biphenylyl)- 4.0 parts 1,4-butanediol Dioctyl sodium sulfosuccinate 0.02 do. (DONSS) Benzoic acid 0.1 do. Sodium cyclamate 0.2 do. Colloidal silicic acid 1.0 do. Polyvinylpyrrolidone 0.1 do. Glycerin 25.0 do. Flavoring 0.1 a do. Distilled water q.s. ad 100.0 parts by vol.

Preparation The DONSS, the benzoic acid, the sodium cyclamate and the polyvinylpyrrolidone are successively dissolved in a sufficient amount of distilled water at C., and the glycerin and colloidal silicic acid are added to the solution. The mixture is cooled to room temperature, the finely pulverized butanediol compound is suspended therein by means of an immersion homogenizer, the flavoring is added, and the composition is diluted with additional distilled water to the indicated volume. ml of the resulting aqueous suspension contain 200 mgm of the butanediol compound and are an oral dosage unit composition with effective antiphlogis- 1 tic action.

Analogous results are obtained when any one of the other compounds embraced by formula I or a non-toxic acid addition salt thereof is substituted for the particular butanol or butanediol compound in Examples 15 through 19. Likewise, the amount of active ingredient in these illustrative examples may be varied to achieve the dosage unit range set forthabove, and the amounts and nature of the inert pharmaceutical carrier ingredients may be varied to meet particular requirements.

While the present invention has been illustrated with the aid of certain specific embodiments thereof, it will be readily apparent to others skilled in the art that the has wherein R 'is halogen,-and

R is hydrogen or halogen. 2. The compound of claim 1 which is 4-(2'--fluoro- 4-biphenylyl)-l-butanol. 

1. A COMPOUND OF THE FORMULA
 2. The compound of claim 1 which is 4-(2''''-fluoro-4''-biphenylyl)-1-butanol. 